Reduced milk triglycerides in mice lacking phosphoenolpyruvate carboxykinase in mammary gland adipocytes and white adipose tissue contribute to the development of insulin resistance in pups.

Obesity and type 2 diabetes are growing problems worldwide in adults and children. In this study, we focused on understanding the patterning of insulin resistance as a result of altered perinatal nutrition. We analyzed mice in which the binding site for PPARgamma was deleted from the promoter of the cytosolic phosphoenolpyruvate carboxykinase gene (Pck1) (PPARE(-/-)). We analyzed pups from dams with the same genotype as well as fostered and cross-fostered pups. Pck1 expression and triglyceride concentration in the milk were measured. The PPARE mutation reduced Pck1 expression in white adipose tissue (WAT) to 2.2% of wild type (WT) and reduced Pck1 expression in whole mammary gland tissue to 1% of WT. The female PPARE(-/-) mice had reduced lipid storage in mammary gland adipocytes and in WAT, resulting in a 40% reduction of milk triglycerides during lactation. Pups from PPARE(-/-) dams had insulin resistance as early as 14 d after birth, a condition that persisted into adulthood. WT pups fostered by PPARE(-/-) dams had lower body weights and plasma insulin concentrations compared with WT pups reared by WT dams. PPARE(-/-) pups fostered by WT dams had improved glucose clearance compared with pups raised by PPARE(-/-) dams. PPARE(+/-) and PPARE(-/-) dams also patterned newborn pups for reduced growth and insulin resistance in utero. Thus, the in utero environment and altered nutrition during the perinatal period cause epigenetic changes that persist into adulthood and contribute to the development of insulin resistance.